The present invention relates to a new method of preparing a matrix-type drug delivery system that allows a controlled-release of drugs, and which has various porosity. The system is manufactured by evaporating solvents from the matrix that is-formed from an emulsion-solution. The emulsion is made by emulsifying an aqueous solution containing a water-soluble drug in a polymer-dissolved organic solution using a surface-active agent.
Emulsion is a stable dispersion of one liquid in a second immiscible liquid, and typically, a surface-active agent is used in order to maintain the emulsion state.
The controlled-release is a characteristic that is capable of improving effects of medical usage, and of reducing its side-effects by making the drugs to be released from the drug-containing substance according to a time schedule. Matrix system means that the drug is evenly or unevenly dissolved or dispersed inside a matrix, in which the matrix substance is continuously aligned.
The release of a water-soluble drug from a non-biodegradable matrix, or from a biodegradable matrix having a low degradation rate typically follows first-order release kinetics, and its release rate decreases gradually as time passes. [ Higuchi T., J. Pharm. Sci. 50, 874xcx9c875 (1961), Higuchi T., Pharm. Sci, 52, 1145xcx9c1149 (1063), Manduit et al, J. controlled Release. 25, 43xcx9c49 (1993)]. In general, the water-soluble drug cannot pass through the hydrophobic matrix. When a water-soluble drug is loaded in a hydrophobic polymer matrix below a percolation threshold, only the drug exposed on its surface is released at an initial period, while most of the drug still remains in the matrix even after a long time has passed. When the water-soluble drug is loaded above the percolation threshold, its release rate depends on the solubility of the drug in the body fluids, and on the diffusion of the drug through the water channels generated by the drug dissolution after the drug is in contact with body fluids. Therefore, in the system loaded with a low molecular compound having a high solubility, a large quantity of initial burst and fast release of the drug are shown. [Siegel et al, J. Controlled Release, 8,223xcx9c236 (1989), Saltzman et al, J. Biophys., 55, 163xcx9c171 (1989)].
In the case of a system in which a water-soluble drug of high osmotic activity is dispersed inside the water-insoluble polymer matrix, the water-soluble drug exposed on the surface is rapidly dissolved so as to form water-channels and is released at the initial period. The portion of the drug away from the water-channels functions as an osmotic pressure-causing material across the wall of the polymer matrix which functions as pseudo-semipermeable membrane. The osmotic pressure gradually breaks the polymer matrix from an outermost to an inside, and the drug is released in a controlled fashion. [Amsden et al, J.Controlled Release. 30, 45xcx9c56 (1994), Amsden B G and Cheng Y., J. Controlled Release, 31,21xcx9c32 (1994)]. Therefore, a drug that causes a high osmotic pressure can be released in a controlled-release fashion, and the remaining drug can be released even if in a case that the drug is loaded below the percolation threshold.
However, when the polymer matrix surrounding the drug is too thick, the possibility of breaking the polymer matrix wall is very low, and the rate of water passing through the polymer down to the drug is decreased, so that the release of the drug is very poor, and the more drug remains in the matrix. [Zhang et al, J.Pharm, Pharmacol. 46, 718xcx9c724 (1994), Amsden B G and Cheng Y., J. Controlled Release, 31, 21xcx9c32 (1994)].
To load a water-soluble drug on a hydrophobic matrix, either simple dispersion of drug particles in an organic polymer solution, or extrusion or compression of the drug-polymer mixture in a solid phase is used. Those loading methods do not allow the even distribution of the drug inside the matrix so that the rate change of the drug release is uneven as time passes.
A method of-manufacturing a porous matrix-type drug delivery system according to the present invention comprises the steps of: dispersing, stirring, and emulsifying an aqueous solution containing a water-soluble drug in an organic solvent in which a polymer compound and a surface active agent are dissolved therein; thereafter forming the resultant into a desirable matrix shape lyophilizing or drying at a low temperature or at a room temperature until the matrix surface is hardened; and drying again to remove water and organic solvents.
The porous matrix-type controlled-release system of the present invention is a matrix substance for oral or non-oral administration of drugs, and can be widely and efficiently used as medical treatment agents because the drugs can be released at a constant rate in a determined period.